LIAI Epitope Validation Center: Characterization of Allergen specific T Cells

描述（由申请人提供：本项目的总体范围是利用充分表征的T细胞过敏原表位的可用性来测试特定假设，这些假设来自对LIAI和Benaroya研究所先前大规模过敏原表位鉴定合同生成的数据的分析。我们以前注意到，在响应蒂莫西草（TG）提取物，正如预期的TH 2细胞因子占主导地位。然而，IFN？IL-17的产生与变应性鼻炎有关，而IL-17的产生与变应性哮喘有关。项目1（Sette PI）将检验以下假设：过敏性疾病的不同阶段（季节内与季节外）、类型（鼻炎与哮喘）和严重程度与T细胞应答的差异幅度以及不同TH亚群的独特相互作用相关。在这里，纵向研究将确定的TH亚群的相对大小的特定的表位在体外和体外扩增后，我们将表征其动力学的外观和相互作用的季节性和疾病的严重程度的函数。项目2（Peters PI）将检验SIT治疗和临床疗效与调节T细胞应答相关的假设。具体来说，我们将测试的假设，SIT治疗影响T细胞反应的一组新的抗原，正在确定由我们的实验室，不承认的IgE反应。对已知和新抗原的应答将与多种表型T细胞标志物一起纵向沿着测量。具体的假设将检查Tfh亚群在调节抗体应答中的作用和IL 10产生细胞在抑制TH 2应答中的作用。项目3（Rao PI）将通过比较从哮喘与过敏性鼻炎患者血液中分离的表位特异性T细胞中的组蛋白修饰和DNA甲基化/羟甲基化模式，鉴定与哮喘发展和严重程度以及SIT治疗相关的表观遗传特征。大量的初步数据表明，转录因子和表观遗传机制之间的相互作用不仅启动免疫细胞分化，而且维持长期的分化状态。因此，我们将检验这一假设，即哮喘的特征是相关疾病相关基因座的长距离表观遗传变化。拟议研究的结果将是产生经验证的过敏原表位数据，并将其传播给科学界。这将实现RFA“过敏原表位研究和验证中心”的目的，为过敏性疾病中T细胞反应的靶点和性质提供新的见解，并为诊断和治疗干预提供潜在的途径。

DESCRIPTION (provided by applicant: The overall scope of this program is to capitalize on the availability of well-characterized T cell allergen epitopes to test specific hypotheses that arose from analysis of the data generated by the previous Large Scale Allergen Epitope Identification contracts, awarded to LIAI and Benaroya Institutes. We previously noted that in response to Timothy Grass (TG) extract, as expected TH2 cytokines predominate. However, IFN? production was associated with allergic rhinitis and IL17 with allergic asthma. Project 1 (Sette PI) will test the hypothesis that different stages (in-season versus out-of-season), types (rhinitis versus asthma) and severities of allergic disease are associated with differential magnitude of T cell responses, and also distinctive interplay of different TH subsets. Here, longitudinal studies will determine the relative size of TH subsets specific for defined epitopes both ex vivo and after in vitro expansion and we will characterize their kinetics of appearance and interplay as a function of seasonality and disease severity. Project 2 (Peters PI) will test th hypothesis that SIT treatment and clinical efficacy is associated with modulating the T cell response. Specifically, we will test the hypothesis that SIT treatment affects T cell responses to a set of novel antigens that are being identified by our laboratory that are not recognized by IgE responses. Responses to both known and novel antigens will be measured longitudinally along with multiple phenotypic T cell markers. Specific hypotheses will examine the role of Tfh subsets in modulating antibody responses and the role of IL10 producing cells in suppressing TH2 responses. Project 3 (Rao PI) will identify epigenetic signatures that correlate with asthma development and severity, as well as SIT treatment, by comparing histone modifications and DNA methylation/ hydroxymethylation patterns in epitope specific T cells isolated from blood of asthmatic versus allergic rhinitis patients. Extensive preliminary data indicates that the interpla between transcription factors and epigenetic mechanisms not only initiates immune cell differentiation but also maintains the long-term differentiated state. Accordingly, we will test th hypothesis that asthma is characterized by long-range epigenetic changes at relevant disease-associated genomic loci. The outcome of the proposed research will be the generation of validated allergen epitope data, and its dissemination to the scientific community. This will fulfil the intent of the RFA "Allergen Epitope Research and Validation Centers", provide new insight into the targets and the nature of T cell responses in allergic disease, and provide potential avenues for diagnostic and therapeutic intervention.